Gammadelta T cells use an alternative receptor for MHCunrestricted[unreadable] recognition and are found in all lymphoid compartments of the human body. The[unreadable] gammadelta (gd) cells recognize cells infected by virus or intracellular bacteria, tumor cells and small[unreadable] molecule antigens. A major question is: Are gd T cells are required for protection against human viral[unreadable] diseases? Previous studies including our own work on HIV disease, provided correlative data for a gd T[unreadable] cell role in viral disease but there are no compelling studies in human or nonhuman primate systems[unreadable] and mechanisms of action have not been defined. Using the model of vaccinia infection, we will[unreadable] determine whether gd T cells are required and define their contributions to protective immunity.[unreadable] Vaccinia is a naturally attenuated vaccine against smallpox in man. The gd T cells are essential for[unreadable] vaccinia immunity in the mouse, where they provide T cell help in the absence of CD4+ cells and[unreadable] promote IgM to IgG isotype switching with the development of neutralizing antibodies although similar[unreadable] functions for g T cells have not been studied in primate species. Our own work revealed a potent,[unreadable] vaccinia-mediated inhibition of human gd T cells. Immune evasion mechanisms generally indicate that[unreadable] the target cells (here gd T cells) are part of the protective response. Studies in this proposal seek to[unreadable] define the mechanism for vaccinia-mediated inhibition of human gd T cells, to test cytokines and TLR[unreadable] agonists for the ability to reverse inhibition, and to perform pilot studies in nonhuman primates for[unreadable] testing the role of gd T cells in the development of vaccinia immunity. Work in this proposal,[unreadable] representing efforts of the Pauza group, the Hoft laboratory in St. Louis University, Bernie Moss at the[unreadable] NIH/NIAID and Yiming Shao from the China CDC, are highly significant for advancing our[unreadable] understanding of gd T cells, for evaluating novel therapeutic approaches to viral disease, for improving[unreadable] vaccine efficacy by stimulating gd T cells, and for efforts to generate safer and more immunogenic[unreadable] vaccinia as smallpox vaccines or as viral vectors. The major human gd T cell subset can be activated in[unreadable] vivo with existing clinical drugs, a direction being tested in novel therapies for cancer, and similar[unreadable] approaches may be useful for viral diseases and vaccination. A subset of human lymphocytes called[unreadable] gammadelta (gd) T cells, are postulated to be important for protective immunity against viral diseases[unreadable] but existing studies provide correlations with disease and have not proven the requirement or defined a[unreadable] mechanism of action for their contribution. Recently, we showed that vaccinia virus (the naturally[unreadable] occurring vaccine against smallpox) potently inhibits gd T cells, suggesting they are part of the[unreadable] mechanism that controls vaccinia infection in man. Our goals are to test the hypothesis that gd T cells[unreadable] are necessary for viral immunity and to pursue the development of new therapies and improved[unreadable] vaccination approaches that incorporate direct stimulation of gd T cells. [unreadable]